1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride of formula (I) below is an important drug having antiproliferative activities such as anti-tumor activity, which can be used for selectively and effectively treating drug resistance caused by tyrosine kinase mutation. Its free base form, i.e., 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one having formula (II) below is identified as CAS Registry Number 1092364-38-9.

The compound of formula (II) may be prepared by, e.g., the method disclosed in Korean Patent No. 1013319, the reaction mechanism thereof being shown in Reaction Scheme 1 below. The compound of formula (II) prepared according to Reaction Scheme 1 may then be reacted with hydrochloric acid to produce the compound of formula (I).

wherein R is halogen.
In Reaction Scheme 1, a compound of formula 10 is subjected to a condensation reaction with formamidine hydrochloride at a high temperature (e.g., 210° C.) to produce a compound of formula 9, which is then subjected to a reaction with L-methionine in an organic acid (e.g., methanesulfonic acid), whereby the methyl group at the position of C-6 of the compound of formula 9 is removed to produce a compound of formula 8.
Subsequently, the compound of formula 8 is subjected to a protection reaction in a base (e.g., pyridine) and anhydrous acetic acid to produce a compound of formula 7, which is then subjected to a reaction with an inorganic acid (e.g., thionylchloride or phosphorous oxychloride) in the presence of a catalytic amount of N,N-dimethylformamide under a reflux condition to produce a compound of formula 6 in hydrochlorate form.
The compound of formula 6 is added under stirring to an ammonia-containing alcohol solution (e.g., a 7N ammonia-containing methanol solution), whereby the acetyl group is removed to produce a compound of formula 5. The compound of formula 5 is subjected to the Mitsunobu reaction with tert-butyl 4-hydroxypiperidin-1-carboxylate to produce a compound of formula 4, which is then subjected to a substitution reaction with aniline in an organic solvent (e.g., 2-propanol or acetonitrile) to produce a compound of formula 3. Diisopropyl azodicarboxylate, diethyl azodicarboxylate or di-t-butyl azodicarboxylate, and triphenylphosphine may be employed for the Mitsunobu reaction. The compound of formula 3 is subjected to a reaction with an organic or inorganic acid (e.g., trifluoroacetic acid or heavy hydrochloric acid) in an organic solvent (e.g., dichloromethane), whereby the t-butoxycarbonyl group is removed to produce a compound of formula 2.
Subsequently, for the production of a compound of formula 1 (i.e., the compound of formula (II) of the present invention), the compound of formula 2 is subjected to an acylation reaction with acryloyl chloride in a mixture of an organic solvent (e.g., tetrahydrofuran) and water, or in dichloromethane, in the presence of an inorganic or organic base (e.g., sodium bicarbonate, pyridine or triethylamine). Alternatively, the compound of formula 2 is subjected to a condensation reaction with acrylic acid in the presence of a coupling agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl europium hexafluorophosphate methanaminium (HATU)).
According to the above method, however, the step for preparing the compound of formula 9 is hazardous since it is conducted at a high temperature without a solvent, and the reaction may not proceed uniformly. Further, an excessive amount of thionyl chloride is used in the step for preparing the compound of formula 5, giving rise to difficulties in the subsequent steps. Hence, this method is not feasible for commercialization.
The main drawbacks of the above method for preparing the compound of formula (I) reside in that the yield of the final product in the acrylic reaction is very low (i.e., 13%) and that the reaction is accompanied by a number of side reactions, which requires a purification step by column chromatography. Also, when the compound of formula 3 is prepared by the Mitsunobu reaction, various by-products would be formed, which necessitates a purification step by column chromatography. Since expensive silica gel and an excessive amount of mobile phase solvents are required in such case, the above method is not feasible for commercialization.
Therefore, the present inventors have endeavored to develop a novel method for preparing the compound of formula (I) in high purity and yield, the method being economical and suitable for commercialization.